NICOLE E. DE LONG – PH.D. THESIS – SSRIs and the risk of T2DM SELECTIVE SEROTONIN REUPTAKE INHIBITORS AND THE RISK OF TYPE 2 DIABETES MELLITUS By NICOLE EVE DE LONG, B.Sc. A Thesis Submitted to the School of Graduate Studies in Partial Fulfillment of the Requirements for the Degree Doctor of Philosophy McMaster University © Copyright by Nicole De Long, December 2015 Ph.D. Thesis – NE De Long; McMaster University – Medical Sciences DOCTORATE OF PHILOSOPHY (2015) Medical Sciences, Physiology and Pharmacology McMaster University Hamilton, Ontario, Canada TITLE: Selective serotonin reuptake inhibitors and the risk of type 2 diabetes mellitus AUTHOR: Nicole Eve De Long, BSc. (Guelph University) SUPERVISOR: Dr. Alison Holloway SUPERVISORY COMMITTEE: Dr. Katherine Morrison Dr. Eva Werstiuk NUMBER OF PAGES: xx, 215 ii Ph.D. Thesis – NE De Long; McMaster University – Medical Sciences Lay Abstract Pregnancy is a window of vulnerability for depression with prevalence rates estimated to be approximately 10%. Guidelines recommend that antidepressant medication should be considered for pregnant women with moderate to severe depression of which selective serotonin reuptake inhibitors (SSRI) are the most common. The aim of this project was to look at SSRI exposure during pregnancy and to determine whether this exposure can predispose the offspring to obesity and/or type 2 diabetes (T2DM). We have found that SSRI use during pregnancy may increase the risk of T2DM and fatty liver in the adult offspring. These findings raise new concerns about the metabolic health of children born to women who take SSRI antidepressants during pregnancy. While these findings suggests a significant outcome in rodents, further investigations are critical to understanding the complexities within this field before suggesting similar outcomes in humans. iii Ph.D. Thesis – NE De Long; McMaster University – Medical Sciences Abstract Major Depressive Disorder (MDD) is a wide spread psychiatric disorder which affects more than 350 million people worldwide. Of the current available treatments, Selective Serotonin Reuptake Inhibitors (SSRIs) are the most commonly prescribed. Long-term SSRI use has been associated with the onset of Type 2 Diabetes (T2DM) in adults. T2DM is driven by beta cell dysfunction and hence we wanted to investigate the mechanism(s) by which SSRIs were causing beta cell demise. We have found that fluoxetine, more commonly known as Prozac®, does in fact disturb beta cell function by inducing mitochondrial dysfunction and thereby oxidative damage. Interestingly, women are twice as likely to experience MDD, and this risk peaks during childbearing years. As a result, up to 1 in 10 pregnancies are complicated with SSRIs. This is an astonishing number considering the long-term effects of these drugs on the children are unknown. Within this thesis I report for the first time, the long-term metabolic outcomes of fetal and neonatal exposure to SSRIs in a rodent model. We have found that antenatal exposure to fluoxetine results in altered glucose homeostasis and impaired insulin sensitivity in the adult offspring. Furthermore we have shown that epigenetic modifications may be implicated in the increased incidence of fatty liver in these offspring. These findings demonstrate a predisposition to the development of obesity and T2DM into adulthood. These findings are novel and have clinical importance with respect to mothers taking these drugs during pregnancy. Within this thesis we are not advising mothers with depression to discontinue medication. We are merely exploring the iv Ph.D. Thesis – NE De Long; McMaster University – Medical Sciences risks in a rodent model while acknowledging that a significant amount of research is required before applying theses results to the human population. v Ph.D. Thesis – NE De Long; McMaster University – Medical Sciences Acknowledgements There are many people that were instrumental to the completion of this thesis. First off I’d like to thank Dr. Alison Holloway for being the strong positive mentor you have been over the past 5 years. Our countless coffee discussions have truly shaped me to be the scientist I am today. I cannot thank you enough for taking a chance on me. My PhD was also supported by my wonderful committee members, Dr. Eva Werstiuk and Dr. Katherine Morrison. Thank you for your continued guidance and support. I had the opportunity to spend quality time with both of you, either through my comprehensive exam or through an independent research unit. I cherished these times greatly. A special thank you needs to be extended to Dr. Daniel Hardy at Western University for his extensive support and encouragement throughout this thesis. My academic family would not be complete without Dr. Sandeep Raha and past and present members of the Raha and Holloway research groups. Thank you for the all the laughs we shared and providing me the boosts and reassurances I needed at times. Most importantly I would like to thank my Mom and Dad for their patience and encouragement throughout my academic pursuits. Your love and support continues to give me the strength and drive to pursue anything I put my mind to – which at times even you two think is crazy. Lastly, I would like to thank my partner in crime, Blake-Joseph Helka. It’s you and me against the world! vi Ph.D. Thesis – NE De Long; McMaster University – Medical Sciences PREFACE This thesis is prepared in the “sandwich” format as outlined in the “Guide for the preparation of Master’s and Doctoral Theses” available through the School of Graduate Studies at McMaster University. Chapter 1 is a general introduction regarding the content of subsequent chapters. Portions of this chapter are published. The body of this thesis consists of 4 chapters (Chapter 2-5), each one an independent study, three of which are published and chapter 5 submitted for publication at the time of thesis submission. The author of this thesis, who is also the first author on all included works, wrote all submitted and published manuscripts included in this thesis. There is a small introduction to each chapter describing the contributions of the other authors. Finally Chapter 6 includes the discussion of this thesis aimed to summarize the conclusions of the thesis and discuss possible future directions along with reviewing the clinical significance of the work. vii Ph.D. Thesis – NE De Long; McMaster University – Medical Sciences TABLE OF CONTENTS Title Page……………………………………………………………………………i Descriptive Notes…………………………………………………………………...ii Lay Abstract……...…………………………………………………………………iii Abstract……………………………………………………………………………..iv Acknowledgements………………………………………………………………....vi Preface ……………………………………………………………………………...vii List of Figures ……………………………………………………………………...xiii List of Tables……………………………………………………………………….xiv Abbreviations…….…………………………………………………………………xv Declaration of Academic Achievement…………………………………………….xvii CHAPTER 1: INTRODUCTION ............................................................................................................. 1 1.1 MAJOR DEPRESSIVE DISORDER ....................................................................................................................... 1 1.1.1 Impact ............................................................................................................................................................. 1 1.1.2 Pathology of Depression & Etiology: A Focus on the Serotonin System ............................. 2 1.2 SELECTIVE SEROTONIN REUPTAKE INHIBITORS .......................................................................................... 6 1.2.1 Prevalence of Antidepressant use ....................................................................................................... 6 1.2.2 SSRI: Mechanism of Action .................................................................................................................... 6 1.3 DEPRESSION AND ITS COMORBIDITIES ........................................................................................................... 8 1.3.1 Bidirectional Relationship Between MDD and T2DM ................................................................ 8 1.3.2 Are Antidepressants the Link? ............................................................................................................ 10 1.4 MECHANISMS UNDERLYING T2DM AND ANTIDEPRESSANT USE ........................................................... 12 1.4.1 Weight Gain ................................................................................................................................................ 12 1.4.2 Insulin Resistance & Fatty Liver ........................................................................................................ 15 1.4.3 Pancreatic Beta Cell Function ............................................................................................................ 17 1.5 ANTIDEPRESSANT USE DURING PREGNANCY .............................................................................................. 20 1.5.1 SSRI Use During Pregnancy: Epidemiologic Evidence ............................................................. 20 1.5.2 SSRI Use During Pregnancy: Human Studies ............................................................................... 23 1.5.3 SSRI Use During Pregnancy: Evidence from Animal Models ................................................. 23 1.6 RATIONALE .......................................................................................................................................................